Toxicity is a major problem in the chemotherapy of cancer. The existence of circadian fluctuation in host toxicity is well established from work in chronopharmacology and chronotoxicology. There are significantly different responses to drugs at different times along the 24-hour day, i.e., hours of changing responsiveness or susceptibility. Can knowledge of rhythmicity in overall host toxicity and of the rhythmic fluctuation in cell division of normal and tumor tissues be effectively used to treat tumor-bearing hosts with maximal toxicity to the tumor and minimal toxicity to the host's "normal" tissues? Our main objectives have been and still are: (1) to identify susceptibility-resistance rhythms to four diverse chemotherapeutic agents (Adriamycin, actinomycin-D, cyclophosphamide and cytosine arabinoside); and (2) to quantify in three groups of mice the rhythmic fluctuation in H3-thymidine incorporation into the DNA of bone marrow, thymus, spleen, gut and liver, and to similarly analyze the mitotic index of liver and corneal epithelium. One group will have adenocarcinoma of the breast, another the Lewis lung carcinoma and the third L 1210 leukemia; each group will be compared with non-tumor-bearing controls. The rhythmicity of DNA will be explored for all tumors, and the effects that tumors of different ages (for each of the three types) have on the variables under study are being determined. Using the data obtained from objectives 1 and 2 above, we have objective 3: to use chronotherapy to attack the tumors by employing the different agents either singly or in combination. To date we have been able to demonstrate advantages of timed treatment by utilizing different protocols designed to give the highest levels of drug when the host is least susceptible and the lowest levels when most susceptible. The advantages demonstrated for mice include an increase in survival time, and in one study it was shown that chronotherapy could increase cure rate in L 1210 leukemia in mice over conventional therapy. The potential for further increasing these advantages is promising. The long-range goal is to gain for man the advantages demonstrated for the mouse. Our aim is to make chronotherapy logistically feasible for man.